6Q5A

Crystal structure of Cryptosporidium hominis CPSF3 in the apo form

Summary for 6Q5A

• Entry DOI: 10.2210/pdb6q5a/pdb
• Related: 6Q55
• Descriptor: Cleavage and Polyadenylation Specificity Factor 3, ZINC ION, GLYCEROL, ... (7 entities in total)
• Functional Keywords: mrna processing factor, metallo-beta-lactamase, beta-casp, oxaborole-inhibitor, rna binding protein
• Biological source: Cryptosporidium hominis
• Total number of polymer chains: 1
• Total formula weight: 54723.86

Authors

Palencia, A.,Swale, C. (deposition date: 2018-12-07, release date: 2019-11-20, Last modification date: 2024-01-24)

Primary citation

Swale, C.,Bougdour, A.,Gnahoui-David, A.,Tottey, J.,Georgeault, S.,Laurent, F.,Palencia, A.,Hakimi, M.A.
Metal-captured inhibition of pre-mRNA processing activity by CPSF3 controls Cryptosporidium infection.
Sci Transl Med, 11:-, 2019

PubMed Abstract: is an intestinal pathogen that causes severe but self-limiting diarrhea in healthy humans, yet it can turn into a life-threatening, unrelenting infection in immunocompromised patients and young children. Severe diarrhea is recognized as the leading cause of mortality for children below 5 years of age in developing countries. The only approved treatment against cryptosporidiosis, nitazoxanide, has limited efficacy in the most vulnerable patient populations, including malnourished children, and is ineffective in immunocompromised individuals. Here, we investigate inhibition of the parasitic cleavage and polyadenylation specificity factor 3 (CPSF3) as a strategy to control infection. We show that the oxaborole AN3661 selectively blocked growth in human HCT-8 cells, and oral treatment with AN3661 reduced intestinal parasite burden in both immunocompromised and neonatal mouse models of infection with greater efficacy than nitazoxanide. Furthermore, we present crystal structures of recombinantly produced CPSF3, revealing a mechanism of action whereby the mRNA processing activity of this enzyme is efficiently blocked by the binding of the oxaborole group at the metal-dependent catalytic center. Our data provide insights that may help accelerate the development of next-generation anti- therapeutics.

PubMed: 31694928
DOI: 10.1126/scitranslmed.aax7161

Experimental method

X-RAY DIFFRACTION (1.55 Å)